The synthesis of prostaglandin analogues

Dixon, Andrew James (1981). The synthesis of prostaglandin analogues. PhD thesis The Open University.



A route was devised which led to the synthesis of 11-deoxyhomoprostacyclin(I), an analogue of prostacyclin (or PGI2) (III). A novel synthetic route to 11-deoxyprostaglandins of the E and F series was also developed.

Natural PGI2 (III) is unstable due to the lability of the enol ether moiety to hydrolysis, but has desirable biological properties, with potential therapeutic applications in the treatment or control of thrombosis. It was hoped that the analogue (I), in which the enol ether moiety has been split up by an extra methylene group, would exhibit similar biological properties. The 11-deoxy analogue(I) was chosen as the initial target since these molecules are easier to synthesise than their 11-hydroxylated counter parts and still exhibit interesting biological properties. The route was devised, however, to be sufficiently flexible so as to allow subsequent synthesis of the 11-hydroxylated analogue(II).

The key step was an organocuprate conjugate addition enolate alkylation reaction. Using various alkylating agents such as allyl bromide or 2-methoxyallyl bromide, gave intermediates which were further functionalised to give the key bicyclic pyran type system. This was then converted by known procedures to the target(I).

An interesting degradative oxidation of one of the intermediates on activated manganese dioxide led to the lactone (IV). This was converted by known procedures to the Corey Lactone an intermediate in the synthesis of ll-deoxy E and F prostaglandins thus constituting a new formal synthesis of these compounds.

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